瓜蒌提取物调控肥大细胞改善糖尿病心肌病心肌纤维化的研究

Diabetic cardiomyopathy is a specific disease process distinct from coronary artery disease and hypertension. The disease features cardiac fibrosis stimulated by hyperglycemia that remodels the left ventricle wall and disrupts contractile functions. Chinese medicine believes that sputum accumulation and stagnation of blood stasis are the main pathogenesis of diabetic myocardial fibrosis.Modern medicine believes that inflammatory cytokines and bioactive enzymes of mast cell, such as chymase, are key mediators of the fibrotic process that may be released from cardiac mast cells during the degranulation process.The extractive of pericarpium trichosanthis has been shown to have better treatment of phlegm and blood of atherosclerosis by the suppression of the inflammatory response.So we hypothesized that the extractive of pericarpium trichosanthis may attenuate cardiac fibrosis of diabetic cardiomyopathy by the suppression of the inflammatory response. Therefore, we induced hyperglycemia in normal mice using streptozotocin and high-fat diet to produce a diabetic cardiomyopathy animal model. Next, we treated the diabetic mice with extractive of pericarpium trichosanthis and then examined their hearts for signs of fibrosis in vivo .In vitro,we focus on the impact of advanced glycation end products modified LDL on the degranulation of mast cell and the intervention effect of the extractive of pericarpium trichosanthis. As the research continues,we could conclude the extractive of pericarpium trichosanthis can attenuate cardiac fibrosis of diabetic cardiomyopathy by mast cell pathway.As this occurs,this research can provide theoretical and experimental basis for the traditional Chinese medicine treatment of diabetic cardiomyopathy.

糖尿病心肌病是糖尿病的一种独立并发症，主要特点之一为高血糖引起的特征性心肌纤维化。中医认为，痰浊闭阻、瘀血阻滞为糖尿病心肌纤维化的主要病机；现代医学认为：糖尿病心肌纤维化与肥大细胞脱颗粒所释放的糜酶、炎症因子等密切相关。瓜蒌提取物已经证明可以治疗痰瘀互结之动脉粥样硬化，其现代医学作用机制与抑制炎症反应有关。据此，我们提出假设，瓜蒌提取物能够治疗糖尿病心肌纤维化，其现代医学作用机制可能与抑制肥大细胞脱颗粒引起的炎症反应有关。为验证这一假说，我们通过制作高脂STZ糖尿病大鼠，给予瓜蒌提取物干预，通过动物实验评价其对糖尿病心肌纤维化的疗效及其对肥大细胞的影响；继之，就高脂糖尿病主要代谢产物晚期糖基化终产物修饰的低密度脂蛋白对肥大细胞脱颗粒进行研究，以及瓜蒌提取物对这一过程的干预作用，探讨瓜蒌提取物抑制糖尿病心肌纤维化的机制，为中药治疗糖尿病心肌纤维化提供理论依据和实验基础。

糖尿病是一种常见的内分泌疾病，糖尿病患者中死于心血管系统疾病的超过70%。糖尿病心肌病（diabetic cardiomyopathy，DCM）是继发于糖尿病中最常见的心血管并发症之一。本课题通过研究以下内容：1、首先，我们通过病例对照研究，研究明确糖尿病性心肌病与循环类胰蛋白酶水平的关系。2、我们在糖尿病小鼠模型上，证实肥大细胞在糖尿病心肌纤维化病变进展中的作用及其肥大细胞稳定剂（DSCG）对心肌纤维化的干预作用，研究瓜蒌提取物瓜蒌皮注射液对糖尿病心肌纤维化的治疗作用。3、在细胞实验中研究AGEs刺激小鼠骨髓源肥大细胞脱颗粒和炎性因子放大的作用，并进一步研究瓜蒌皮注射液对AGEs刺激肥大细胞激活的影响。得到主要研究结论： 1）DCM患者血浆类胰蛋白酶水平高于ICM组和正常对照组，且与空腹血糖呈正相关。2）STZ诱导糖尿病小鼠在成模12周后发现明显的心肌纤维化，伴心肌肥大细胞数目的增加和激活，纤维化相关指标α-SMA和TNF-β的蛋白表达增加；肥大细胞膜稳定剂DSCG对心肌纤维化有抑制作用；瓜蒌皮注射液可减少心肌组织中肥大细胞的数目，抑制肥大细胞激活，改善心肌纤维化。3）瓜蒌皮注射液可以抑制AGEs-LDL刺激mBMMCs的类胰蛋白酶的释放率和炎性因子（TNF-α，IL-1，IL-6，IFN-γ）的mRNA的表达。实验证明化瘀类中药瓜蒌可以抑制炎症反应，治疗糖尿病心脏病。